CDC-like kinase 4 deficiency contributes to pathological cardiac hypertrophy by modulating NEXN phosphorylation

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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model

Published on: August 8, 2022

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Jian Huang1,2,3, Luxin Wang1,2,3, Yunli Shen1,2

  • 1Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.

Nature Communications
|July 30, 2022
PubMed

Insights

CDC-like kinase 4 (CLK4) regulates heart health by phosphorylating nexilin (NEXN). CLK4 deficiency causes pathological cardiac hypertrophy and heart failure, highlighting CLK4 as a potential therapeutic target.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Biochemistry

Background:

  • Kinase-catalyzed phosphorylation is vital in pathological cardiac hypertrophy.
  • The role of CDC-like kinase 4 (CLK4) in cardiac function and failure requires elucidation.

Purpose of the Study:

  • To investigate the role of CLK4 in cardiomyocyte hypertrophy and heart failure.
  • To identify the downstream targets and mechanisms regulated by CLK4 in the heart.

Main Methods:

  • Utilized knockdown and overexpression of CLK4 in cardiomyocytes and cardiac-specific knockout mice.
  • Identified nexilin (NEXN) as a direct substrate of CLK4 using biochemical assays.
  • Employed phosphorylation-mimic mutants to assess functional rescue.

Main Results:

  • CLK4 deficiency induced pathological cardiomyocyte hypertrophy and cardiac dysfunction in mice.
  • CLK4 overexpression protected against hypertrophy.
  • Nexilin (NEXN) was identified as a direct substrate, and its phosphorylation by CLK4 reversed hypertrophy.

Conclusions:

  • CLK4 regulates cardiac function and prevents pathological hypertrophy via NEXN phosphorylation.
  • CLK4 deficiency contributes to heart failure, positioning CLK4 as a potential therapeutic target.

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